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PubMed2003

Toxic responses of the lung to inhaled pollutants: benefits and limitations of lung-disease models.

The widely accepted notion that certain individuals are more susceptible to air pollutants than others has been revitalized by recent epidemiology that strongly suggests that the elderly, particularly those with underlying cardiopulmonary diseases (e.g. chronic obstructive pulmonary disease (COPD), infection), and children with asthma are more susceptible to the adverse outcomes associated with ambient particulate matter (PM). Pulmonary toxicologists have adopted 'susceptibility' as an issue that can be approached experimentally and have begun to develop as well as study more relevant animal models. These models may have specific genetic traits or cardiopulmonary impairments analogous to human diseases. The goal is to identify potential susceptibility characteristics and elucidate whether responsiveness is due to impair compensation or some unique mechanisms. Several rodent models have been used with PM: pulmonary vasculitis, bronchitis, COPD, allergic asthma, infectious lung diseases, systemic hypertension, and congestive heart disease. Transgenic and knockout mice are of growing interest but have seen limited use in air pollutants studies, with primary interest being directed to specific mechanistic questions. No model should be used without careful consideration of its strengths and limitations. However, when interpreted in the context of field and epidemiology findings, they may reveal generic susceptibility attributes or useful biomarkers.

Administration, Inhalation↗
PubMed2000

Genes and addiction.

Drug addiction, like all psychiatric disorders, is defined solely in behavioural terms. For example, addiction can be considered a loss of control over drug-taking, or compulsive drug-seeking and -taking despite horrendous consequences. Abnormal behaviours are a consequence of aberrant brain function, which means that it is a tangible goal to identify the biological underpinnings of addiction. The genetic basis of addiction encompasses two broad areas of enquiry. One of these is the identification of genetic variation in humans that partly determines susceptibility to addiction. The other is the use of animal models to investigate the role of specific genes in mediating the development of addiction. Whereas recent advances in this latter effort are heartening, a major challenge remains: to understand how the many genes implicated in rodent models interact to yield as complex a phenotype as addiction.

Alcoholism↗
PubMed2004

D5 dopamine receptor knockout mice and hypertension.

Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. All of the five dopamine receptor genes (D1, D2, D3, D4, and D5) expressed in mammals and some of their regulators are in loci linked to hypertension in humans and in rodents. Under normal conditions, D1-like receptors (D1 and D5) inhibit sodium transport in the kidney and the intestine. However, in the Dahl salt-sensitive and spontaneously hypertensive rats, and humans with essential hypertension, the D1-like receptor-mediated inhibition of sodium transport is impaired because of an uncoupling of the D1-like receptor from its G protein/effector complex. The uncoupling is genetic, and receptor-, organ-, and nephron segment-specific. In human essential hypertension, the uncoupling of the D1 receptor from its G protein/effector complex is caused by an agonist-independent serine phosphorylation/desensitization by constitutively active variants of the G protein-coupled receptor kinase type 4. The D5 receptor is also important in blood pressure regulation. Disruption of the D5 or the D1 receptor gene in mice increases blood pressure. However, unlike the D1 receptor, the hypertension in D5 receptor null mice is caused by increased activity of the sympathetic nervous system, apparently due to activation of oxytocin, V1 vasopressin, and non-N-methyl D-aspartate receptors in the central nervous system. The cause of the activation of these receptors remains to be determined.

Animals↗
PubMed2003

Glucuronidation of 1'-hydroxyestragole (1'-HE) by human UDP-glucuronosyltransferases UGT2B7 and UGT1A9.

Estragole (4-allyl-1-methoxybenzene) is a naturally occurring food flavoring agent found in basil, fennel, bay leaves, and other spices. Estragole and its metabolite, 1'-hydroxyestragole (1'-HE), are hepatocarcinogens in rodent models. Recent studies from our laboratory have shown that glucuronidation of 1'-HE is a major detoxification pathway for estragole and 1'-HE, accounting for as much as 30% of urinary metabolites of estragole in rodents. Therefore, this study was designed to investigate the glucuronidation of 1'-HE in human liver microsomes in vitro and identify the specific uridine diphosphate glucuronosyltransferase (UGT) isoforms responsible for 1'-HE glucuronidation. The formation of the glucuronide of 1'-HE (1'-HEG) followed atypical kinetics, and the data best fit to a Hill equation, resulting in apparent kinetic parameters of Km = 1.45 mM, Vmax = 164.5 pmoles/min/mg protein, and n = 1.4. There was a significant intersubject variation in 1'-HE glucuronidation in 27 human liver samples, with a CV of 42%. A screen of cDNA expressed UGT isoforms indicated that UGT2B7 (83.94 +/- 0.188 pmols/min/mg), UGT1A9 (51.36 +/- 0.72 pmoles/min/mg), and UGT2B15 (8.18 +/- 0.037 pmoles/min/mg) were responsible for 1'-HEG formation. Glucuronidation of 1'-HE was not detected in cells expressing UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, and UGT1A10. 1'-HE glucuronidation in 27 individual human liver samples significantly (p < 0.05) correlated with the glucuronidation of other UGT2B7 substrates (morphine and ibuprofen). These results imply that concomitant chronic intake of therapeutic drugs and dietary components that are UGT2B7 and/or UGT1A9 substrates may interfere with estragole metabolism. Our results also have toxicogenetic significance, as UGT2B7 is polymorphic and could potentially result in genetic differences in glucuronidation of 1'-HE and, hence, toxicity of estragole.

Analgesics, Opioid↗
PubMed2005

Historic perspectives and recent advances in major animal models of hypertension.

Hypertension and related cardiovascular diseases are the leading causes of death in many countries. The etiology of human essential hypertension is largely unknown. It is highly likely that hypertension is a complex and multifactorial disease resulting from the interaction of multiple genetic and environmental factors. Animal models of hypertension have been proved to be useful to study the pathogenesis of, and to find a new therapy for, hypertension. The aim of this article is to briefly review the most widely used rodent models of experimental hypertension, including history and recent advances. These models are classified as genetically-induced, environmentally-induced, pharmacologically-induced, and renal-induced hypertension according to the way of induction; the typical representatives of each of these major types of experimental hypertension are spontaneous hypertension, cold-induced hypertension, DOCA-salt-induced hypertension, and renal-induced hypertension, respectively. The processes of induction of hypertension, possible pathogenesis, characteristics, advantages, and limitations of these animal models are reviewed. In addition, the clinical implications of the above experimental models of hypertension are addressed.

Animals↗
PubMed2003

COX-2 inhibition and retinal angiogenesis in a mouse model of retinopathy of prematurity.

PURPOSE: The prostaglandin-cyclooxygenase (COX) pathway influences new blood vessel growth in a variety of tissues. This study was conducted to determine the cellular location of COX-2 in the retina and whether the inhibition of COX-2 would reduce retinal angiogenesis in a rodent model of retinopathy of prematurity (ROP). METHODS: ROP was induced in C57BL/6 mice by exposing 7-day-old mice to 75% oxygen (hyperoxia) for 5 days followed by 5 days in room air (relative hypoxia and retinal angiogenesis). Normal mice were those with a normally developing retinal vasculature exposed to room air from birth until postnatal day (P)17. The COX-2 inhibitor, rofecoxib (15 mg/kg body weight intraperitoneally) was administered to normal and ROP mice from P12 to P17. Immunohistochemistry for COX-2 was performed on retinas from all groups by the avidin-biotin method. Histologic methods were used to count blood vessel profiles (BVPs) in the inner retina (inner limiting membrane, ganglion cell layer, and inner plexiform layer) with a masked approach. RESULTS: Intense COX-2 immunolabeling was specifically localized to ganglion cells and blood vessels of all mice retinas. In ROP mice, COX-2 immunolabeling was detected on blood vessels extending into the vitreous cavity. Quantitation of BVPs in the inner retina revealed an increase in untreated ROP mice compared with untreated normal mice (P < 0.001). Rofecoxib decreased BVPs by approximately 45% in normal mice and 37% in ROP mice. CONCLUSIONS: COX-2 is localized to sites associated with retinal blood vessels. The finding that the selective COX-2 inhibitor, rofecoxib, attenuated the retinal angiogenesis that accompanies ROP, and normal retinal development indicates that COX-2 plays an important role in blood vessel formation in the retina.

Animals↗
PubMed2004

Selective ganglion cell functional loss in rats with experimental glaucoma.

PURPOSE: To characterize retinal functional consequences of elevated intraocular pressure (IOP) in a rat model of experimental glaucoma. METHODS: Unilateral elevation of IOP was produced by hypertonic saline injection into an episcleral vein in 20 adult male Brown-Norway rats. IOP was measured in both eyes of awake animals four to five times per week. After 5 weeks, animals were dark adapted overnight (>12 hours) and full-field electroretinograms (ERGs) were obtained simultaneously from both eyes. Scotopic ERG stimuli were brief white flashes (-6.64-2.72 log cd-s/m(2)). Photopic responses were also obtained (0.97-2.72 log cd-s/m(2)) after 15 minutes of light adaptation (150 cd/m(2)). Eyes were processed the following day for histologic evaluation by light microscopy, including masked determination of optic nerve injury grade (ONIG; 1, normal; 5, severe, diffuse damage). RESULTS: Among experimental eyes, the group average IOP (+/-SD) was 34.5 +/- 4.1 mm Hg, whereas the average for control eyes was 28.1 +/- 0.5 mm Hg (t = 7.1, P < 0.0001). The average ONIG for experimental and control eye groups, respectively, was 3.4 +/- 1.7 and 1.0 +/- 0.02 (t = 6.3, P < 0.0001). The ONIG increased with mean IOP in experimental eyes (r(2) = 0.78, P < 0.0001) and was unrelated to mean IOP in control eyes (r(2) = 0.09, P = 0.18). In experimental eyes with relatively mild IOP elevation (mean IOP < 31 mm Hg) and no structural (histologic) damage to the optic nerve evident by light microscopy (ONIG = 1.1 +/- 0.2, n = 5), there was a selective reduction of the positive scotopic threshold response (pSTR; P < 0.001), whereas other ERG components remained unaltered. In four of the five eyes, pSTR amplitude was reduced by more than 50%, whereas all five had normal scotopic a-wave, b-wave, and OP amplitudes. Eyes with mean IOP of more than 35 mm Hg had reduced a-wave, b-wave, and oscillatory potential (OP) amplitudes. CONCLUSIONS: As demonstrated by prior studies, selective loss of the pSTR is indicative of selective retinal ganglion cell (RGC) injury. In this rat model of experimental glaucoma, selective RGC functional injury occurred before the onset of structural damage, as assessed by light microscopy of optic nerve tissue. The highest IOP levels resulted in nonselective functional loss. Thus, in rodent models of experimental glaucoma, lower levels of chronically elevated IOP may be more relevant to human primary chronic glaucoma.

Animals↗
PubMed2006

Low-dose dopamine agonist administration blocks vascular endothelial growth factor (VEGF)-mediated vascular hyperpermeability without altering VEGF receptor 2-dependent luteal angiogenesis in a rat ovarian hyperstimulation model.

No specific treatment is available for ovarian hyperstimulation syndrome (OHSS), the most important complication in infertile women treated with gonadotropins. OHSS is caused by increased vascular permeability (VP) through ovarian hypersecretion of vascular endothelial growth factor (VEGF)-activating VEGF receptor 2 (VEGFR-2). We previously demonstrated in an OHSS rodent model that increased VP was prevented by inactivating VEGFR-2 with a receptor antagonist (SU5416). However, due to its toxicity (thromboembolism) and disruption of VEGFR-2-dependent angiogenic processes critical for pregnancy, this kind of compound cannot be used clinically to prevent OHSS. Dopamine receptor 2 (Dp-r2) agonists, used in the treatment of human hyperprolactinemia including pregnancy, inhibit VEGFR-2-dependent VP and angiogenesis when administered at high doses in animal cancer models. To test whether VEGFR-2-dependent VP and angiogenesis could be segregated in a dose-dependent fashion with the Dp-r2 agonist cabergoline, a well-established OHSS rat model supplemented with prolactin was used. A 100 microg/kg low-dose Dp-r2 agonist cabergoline reversed VEGFR-2-dependent VP without affecting luteal angiogenesis through partial inhibition of ovarian VEGFR-2 phosphorylation levels. No luteolytic effects (serum progesterone levels and luteal apoptosis unaffected) were observed. Cabergoline administration also did not affect VEGF/VEGFR-2 ovarian mRNA levels. Results in the animal model and the safe clinical profile of Dp-r2 agonists encouraged us to administer cabergoline to oocyte donors at high risk for developing the syndrome. Prophylactic administration of cabergoline (5-10 microg/kg x d) decreased the occurrence of OHSS from 65% (controls) to 25% (treatment). Therefore, a specific, safe treatment for OHSS is now available.

Animals↗
PubMed2006

Insulin signal mimicry as a mechanism for the insulin-like effects of vanadium.

Among several metals, vanadium has emerged as an extremely potent agent with insulin-like properties. These insulin-like properties have been demonstrated in isolated cells, tissues, different animal models of type I and type II diabetes as well as a limited number of human subjects. Vanadium treatment has been found to improve abnormalities of carbohydrate and lipid metabolism and of gene expression in rodent models of diabetes. In isolated cells, it enhances glucose transport, glycogen and lipid synthesis, and inhibits gluconeogenesis and lipolysis. The molecular mechanism responsible for the insulin-like effects of vanadium compounds have been shown to involve the activation of several key components of insulin-signaling pathways that include the mitogen-activated-protein kinases (MAPKs) extracellular signal-regulated kinase 1/2 (ERK1/2) and p38MAPK, and phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB). It is interesting that the vanadium effect on these signaling systems is independent of insulin receptor protein tyrosine kinase activity, but it is associated with enhanced tyrosine phosphorylation of insulin receptor substrate-1. These actions seem to be secondary to vanadium-induced inhibition of protein tyrosine phosphatases. Because MAPK and PI3-K/PKB pathways are implicated in mediating the mitogenic and metabolic effects of insulin, respectively, it is plausible that mimicry of these pathways by vanadium serves as a mechanism for its insulin-like responses.

Animals↗
PubMed2002

Rosiglitazone improves insulin resistance, lipid profile and promotes adiposity in a genetic model of metabolic syndrome X.

RSG is a member of the TZD group of drugs widely used in treatment of type 2 diabetes. The underlying mechanism of TZD action in insulin-sensitive tissues is not fully understood. In this study we show that 14-day RSG administration in a new rodent model of metabolic syndrome X, polydactylous rat strain (PD/Cub), substantially improves its lipid profile (serum TGs 4.20 +/- 0.23 vs 2.34 +/- 0.14 mmol/l, P < 0.0001; FFA 0.46 +/- 0.05 vs 0.33 +/- 0.02 mmol/l, P = 0.017), diminishes the liver TG depots (15.76 +/- 0.60 vs 8.44 +/- 0.55 micromol/g, P < 0.0001), serum insulin concentrations (1.10 +/- 0.08 vs 0.63 +/- 0.02 nmol/l, P < 0.0001) and promotes visceral adiposity (adiposity index 1.28 +/- 0.03 vs 1.85 +/- 0.07, P < 0.0001). No changes were observed in serum or liver concentrations of cholesterol. Concomitantly, both basal and insulin-stimulated glycogen synthesis in red-fibre type muscle (m. soleus) was enhanced, as well as glucose uptake into adipose tissue. However, glucose oxidation in soleus (basal and insulin-stimulated) remained unchanged. In consent with previously published data we suggest the current pharmacogenetic study as a further proof of substantial influence of genetic background on the physiological outcome of TZD therapy.

Adipose Tissue↗
PubMed1995

FDA Guidelines and animal models for osteoporosis.

The recent FDA Guidelines For Preclinical and Clinical Evaluation of Agents Used in the Treatment or Prevention of Postmenopausal Osteoporosis (1994) delineate specific preclinical animal models to demonstrate the efficacy and safety of new, potential agents for osteoporosis therapy. The Guidelines recommend that agents be evaluated in two animal species, including the ovariectomized (OVX) rat and in a second non-rodent model. We have performed a series of studies to determine whether the recommended OVX rat models, endpoints, and study design adequately address the efficacy and safety of therapeutic agents for the treatment or prevention of osteoporosis. Our study results indicate that the rat OVX model mimics postmenopausal cancellous bone loss when examined over relatively short periods of time. These data illustrate that cancellous bone turnover increases following OVX and this increased bone turnover produces bone loss. Estrogen completely blocks the activation of bone turnover and bone loss. Thus, our data suggest that the rat OVX model in the proximal tibia, distal femur, and lumbar vertebrae mimics conditions in the postmenopausal woman and is suitable for the evaluation of potential therapeutic agents for the prevention of osteoporosis. However, when the duration of the studies extends to 12 months as suggested by the Guidelines, the indices of cancellous bone turnover return to the value of sham controls, although the trabecular bone volume remains lower than that of sham controls in OVX rats. Therefore, it is difficult to determine the effects of potential therapeutic agents on the bone turnover in estrogen deficient conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed2006

The human fetal adrenal cortex and the window of sexual differentiation.

Understanding normal development is fundamental to appreciating postnatal morphology, physiology and, in some instances, pathophysiology. Developmental biology tends to interrogate models in nonprimate species, for instance the mouse, where genetic manipulation gives privileged insight into the function of particular genes. Some human developmental processes, as occur in the adrenal gland, are not faithfully reproduced in these rodent models, yet have an impact on the pathophysiology and treatment of endocrine disorders, such as congenital adrenal hyperplasia. In this setting, in vitro research of normal human development complements clinical investigation of patients born with congenital disorders.

Adrenal Cortex↗
PubMed1998

Different response to balloon angioplasty of carotid and coronary arteries: effects on acute platelet deposition and intimal thickening.

PTCA is a well-established intervention to reduce the severity of atherosclerotic coronary stenosis. Its primary success rate is seriously handicapped by the high incidence of late restenosis. Given the clinical and social importance of this proliferative process, new strategies are needed to prevent or reduce restenosis. Several animal models as well as different arteries have been used to study neointimal proliferation after arterial injury. A number of agents have shown to reduce neointimal proliferation after arterial injury in the carotids and iliac arteries of rodent models. Unfortunately, these results have not been replicated in humans. We have compared the acute and late response to vascular injury of the carotid and coronary arteries in the pig. Arterial injury was induced by performing balloon angioplasty of the carotid (elastic) and coronary (muscular) arteries in swine. Acute platelet-thrombus formation was evaluated by quantitation of Indium-labeled platelets deposited on the injured segments 1 h after procedure. Measurement of intimal area was performed by morphometry of the most stenotic cross-section at 28 days after balloon angioplasty. Platelet deposition after mild and severe injury in carotids (4 +/- 1 and 56 +/- 13 x 10(6) platelets/cm2, respectively) and coronaries (15 +/- 5 and 141 +/- 20 x 10(6) platelets/cm2, respectively) are significantly greater in deep, than in mild injury (P < 0.005), and significantly greater in coronary than in carotid arteries after deep injury (P < 0.05). Likewise, late neointima formation was significantly greater (P < 0.05) after mild and severe injury in coronary (17 +/- 0.5 and 56 +/- 2%, respectively) than in carotid arteries (5 +/- 0.5 and 12 +/- 1%, respectively). Acute platelet-thrombus formation and late neointimal thickening are modulated by the degree of injury induced during the interventions; and after disruption of the internal elastic lamina, coronary arteries always had significantly more acute thrombus and neointimal thickening. This study emphasizes the importance of the animal species, the type of injury and the artery chosen for studies on restenosis post interventions.

Acute Disease↗
PubMed2002

[Neurogenic inflammation. II. pathophysiology and clinical implications].

Neurogenic inflammation is elicited by activation of unmyelinated sensory neurons through noxious stimuli and subsequent release of neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) from peripheral nerve endings. The nerve-mediated inflammatory responses in the tissue consist of hyperaemia and oedema which under some circumstances may be accompanied by pain. Neurogenic inflammation has been implicated in the pathophysiology of various human diseases with uncertain etiology. Signs of inflammation and hyperalgesia associated with chronic pain syndromes such as migraine, arthritis and complex regional pain syndrome resemble the characteristics of neurogenic inflammation. By extrapolation of convincing evidence obtained in rodent models, neurogenic inflammation is assumed to contribute to diseases of the respiratory system, gastrointestinal tract, urogenital tract, and skin in humans. Since, however, highly selective substance P receptor antagonists, found to be effective against inflammation in rodents, failed to inhibit inflammatory processes in clinical trials, the hypothesis of an involvement of neurogenic inflammation in human diseases is discussed critically in this review. Beyond its primarily inflammatory character neurogenic inflammation can be regarded as a mechanism that activates protective responses, thus bringing about a first line of defence to maintain the integrity of the tissue and to contribute to tissue repair.

Animals↗
PubMed1993

Animal models of inherited epilepsy.

A significant proportion of the childhood epilepsies have a genetic component. Therefore, animal models that can be bred for seizure expression may provide important information regarding the mechanisms by which molecular defects result in the neuronal hyperexcitability states collectively termed "epilepsy." Because of the rate and ease of breeding, rodent models are the most commonly used. The genetically epilepsy-prone rat has motor seizures in response to auditory stimuli. It is likely that the seizures are generated in the inferior colliculus because of an abnormality in the noradrenergic system. The seizure predisposition is inherited as an autosomal dominant trait. The genetic absence epilepsy rat has age-related spontaneous seizures characterized by motor arrest and head drops that are correlated with generalized spike-wave on the electroencephalogram (EEG). The seizure generating mechanism appears to be located in the lateral thalamic nuclei. The epileptic mongolian gerbil demonstrates behavioral arrest followed by myoclonic, tonic, and tonic-clonic seizures in response to unfamiliar environments. The underlying neuroanatomy involves hippocampal-cortical interactions indicative of a partial epilepsy. The tottering mouse has absence and myoclonic seizures, a 6- to 7-Hz ictal spike-wave EEG, and noradrenergic hyperinnervation that are linked to a mutation on chromosome 8. Hippocampal network hyperexcitability has been found with normal neuronal intrinsic properties. Stargazer is a mouse mutant with almost identical clinical and electrographic features as found in tottering. However, the genetic defect is located on chromosome 15 and no abnormalities of norepinephrine have been discovered. The El mouse demonstrates ictal automatisms in response to vestibular stimulation. Metabolic and structural abnormalities have been found in the hippocampus. Linkage to chromosomes 9 and 2 have been reported recently. The dilute brown agouiti mouse demonstrates motor seizures in response to auditory stimuli. Chromosomes 4 and 17 are linked to seizure expression. Thus, a variety of models exist to study the genetic, biochemical, structural and electrophysiological mechanisms that underlie the predisposition and expression of the inherited epilepsies.

Animals↗
PubMed2006

From bedside to bench and back again: research issues in animal models of human disease.

To improve outcomes for patients with many serious clinical problems, multifactorial research approaches by nurse scientists, including the use of animal models, are necessary. Animal models serve as analogies for clinical problems seen in humans and must meet certain criteria, including validity and reliability, to be useful in moving research efforts forward. This article describes research considerations in the development of rodent models. As the standard of diabetes care evolves to emphasize intensive insulin therapy, rates of severe hypoglycemia are increasing among patients with type 1 and type 2 diabetes mellitus. A consequence of this change in clinical practice is an increase in rates of two hypoglycemia-related diabetes complications: hypoglycemia-associated autonomic failure (HAAF) and resulting hypoglycemia unawareness. Work on an animal model of HAAF is in an early developmental stage, with several labs reporting different approaches to model this complication of type 1 diabetes mellitus. This emerging model serves as an example illustrating how evaluation of validity and reliability is critically important at each stage of developing and testing animal models to support inquiry into human disease.

Animal Experimentation↗
PubMed2001

Convection-enhanced delivery in intact and lesioned peripheral nerve.

OBJECT: Although the use of multiple agents is efficacious in animal models of peripheral nerve injury, translation to clinical applications remains wanting. Previous agents used in trials in humans either engendered severe side effects or were ineffective. Because the blood-central nervous system barrier exists in nerves as it does in the brain, limited drug delivery poses a problem for translation of basic science advances into clinical applications. Convection-enhanced delivery (CED) is a promising adjunct to current therapies for peripheral nerve injury. In the present study the authors assessed the capacity of convection to ferry macromolecules across sites of nerve injury in rat and primate models, examined the functional effects of convection on the intact nerve, and investigated the possibility of delivering a macromolecule to the spinal cord via retrograde convection from a peripherally introduced catheter. METHODS: The authors developed a rodent model of convective delivery to lesioned sciatic nerves (injury due to crush or laceration in 76 nerves) and compared the results to a smaller series of five primates with similar injuries. In the intact nerve, convective delivery of vehicle generated only a transient neurapraxic deficit. Early after injury (postinjury Days 1, 3, 7, and 10), infusion failed to cross the site of injury in crushed or lacerated nerves. Fourteen days after crush injury, CED of radioactively-labeled albumin resulted in perfusion through the site of injury to distal growing neurites. In primates, successful convection through the site of crush injury occurred by postinjury Day 28. In contrast, in laceration models there was complete occlusion of the extracellular space to convective distribution at the site of laceration and repair, and convective distribution in the extracellular space crossed the site of injury only after there was histological evidence of completion of nerve regeneration. Finally, in two primates, retrograde infusion into the spinal cord through a peripheral nerve was achieved. CONCLUSIONS: Convection provides a safe and effective means to deliver macromolecules to regenerating neurites in crush-injured peripheral nerves. Convection block in lacerated and suture-repaired nerves indicates a significant intraneural obstruction of the extracellular space. a disruption that suggests an anatomical obstruction to extracellular and, possibly, intraaxonal flow, which may impair nerve regeneration. Through peripheral retrograde infusion, convection can be used for delivery to spinal cord gray matter. Convection-enhanced delivery provides a promising approach to distribute therapeutic agents to targeted sites for treatment of disorders of the nerve and spinal cord.

Albumins↗
PubMed2005

Experimental animal models of encapsulating peritoneal sclerosis.

Encapsulating peritoneal sclerosis (EPS) is an infrequent, but extremely serious complication of long-term peritoneal dialysis. The cause of EPS is unclear, but the low incidence suggests that it is most likely multifactorial. The elucidation of developmental pathways and predictive markers of EPS would facilitate the identification and management of high-risk patients. Animal models are often used to define pathways of disease progression and to test strategies for treatment and prevention in the patient population. Ideally such models could help to define the cause of EPS and its developmental pathways, to facilitate the identification of contributing factors and predictive markers, and to provide a system to test therapeutic strategies. Researchers have studied several rodent models of EPS that rely on chronic chemical irritation (for example, bleach, low-pH solution, chlorhexidine gluconate) to induce peritoneal sclerosis and abdominal encapsulation. Development in all models is progressive, with inflammation giving way to peritoneal fibrosis or sclerosis with accumulating membrane damage, culminating in cocoon formation. Microscopic findings are similar to those proposed as diagnostic criteria for clinical EPS: an initial inflammatory infiltrate and submesothelial thickening, collagen deposition, and activation and proliferation of peritoneal fibroblasts. The potential to block progression of peritoneal sclerosis in these models by anti-inflammatory, antifibrotic, and anti-angiogenic agents, and by inhibitors of the renin-angiotensin system have been demonstrated. Animal models based on clinically relevant risk factors (for example, uremia, peritonitis, and long-term exposure to dialysis solutions) now represent the next step in model development.

Animals↗